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Key Signaling Pathways in the Cardiovascular System

  • Fábio TrindadeEmail author
  • Inês Falcão-Pires
  • Andreas Kavazis
  • Adelino Leite-Moreira
  • Daniel Moreira-Gonçalves
  • Rita Nogueira-FerreiraEmail author
Chapter
  • 73 Downloads

Abstract

The activity of the heart and vessels is permanently modulated in response to electrical, mechanical and chemical signals to maintain cardiovascular system homeostasis. Some effects are rapidly manifested (e.g. contraction after an electrical stimulus), while others are observed at long-term (e.g. hypertrophy resulting from gene expression modulation). In any case, an orchestrated set of events follows from receptor to intracellular messengers and effectors via complex signaling routes. These include neurohumoral signaling targeting G protein-coupled receptors (such as adrenaline, angiotensin II and endothelin-1 receptors), growth factor pathways initiated at tyrosine (including insulin, vascular endothelial growth factor and fibroblast growth factor) or serine/threonine kinase receptors (transforming growth factor-β) or even direct intracellular/nuclear pathways (triggered by calcium, nitric oxide or thyroid hormones). Herein, the signaling pathways taking place in cardiomyocytes, endothelial cells, vascular smooth muscle cells and fibroblasts, mainly involved in the regulation of cardiac contraction, vasorelaxation, mechanotransduction, cell survival and hypertrophy are described. Finally, the role of extracellular matrix in cardiac remodeling and fibrosis is reviewed.

Keywords

Cardiomyocytes Contraction Fibrosis Hypertrophy Intracellular signaling Vascular cells 

Abbreviations

AC

Adenylate cyclase

AKAP

A-kinase anchor protein

ALK

Activin receptor-like kinases

Ang II

Angiotensin II

ANP

Atrial natriuretic peptide

β-AR

β-adrenergic receptors

BNP

B-type natriuretic peptide

Ca2+

Calcium

CaM

Calmodulin

CaMKII

Ca2+/CaM-dependent protein kinase II

cAMP

Cyclic adenosine monophosphate

cGMP

Cyclic guanosine monophosphate

CREB

cAMP-responsive element-binding protein

DAG

Diacylglycerol

ECC

Excitation-contraction coupling

ECM

Extracellular matrix

ECs

Endothelial cells

EGF

Epidermal growth factor

eNOS

Nitric oxide synthase, endothelial

ERK

Extracellular signal-regulated protein kinase

ET-1

Endothelin-1

ETA

Endothelin receptor A

ETB

Endothelin receptor B

ETC

Excitation-transcription coupling

FAK

Focal adhesion kinase

FGF

Fibroblast growth factor

FGFR

Fibroblast growth factor receptor

FoxO

Forkhead box protein O

GC

Guanylate cyclase

GPCRs

G protein-coupled receptors

GSK3β

Glycogen synthase kinase-3β

HB-EGF

Heparin-binding EGF-like growth factor

HDAC

Histone deacetylase

HIF-1α

Hypoxia-inducible factor-1α

IGF

Insulin-like growth factor

IP3

Inositol 1,4,5-trisphosphate

IRS

Insulin receptor substrate

JNK

c-Jun N terminal kinase

LTCC

Voltage-dependent L-type calcium channels

MLC

Myosin light chain

MLCK

Myosin light chain kinase

MLCP

Myosin light chain phosphatase

MMP

Matrix metalloproteinase

MyBP-C

Myosin-binding protein C

NCX

Sodium/calcium exchanger

NFAT

Nuclear factor of activated T-cells

NF-κB

Nuclear factor NF-kappa-B

NO

Nitric oxide

NRG1

Neuregulin 1

PDGF

Platelet-derived growth factor

PDGFR

PDGF receptor

PI-3K

Phosphatidylinositol 3-kinase

PIP2

Phosphatidylinositol 4,5-bisphosphate

PIP3

Phosphatidylinositol 3,4,5-trisphosphate

PKA

Protein kinase A

PKC

Protein kinase C

PKG

Protein kinase G

PLB

Phospholamban

PLC

Phospholipase C

RAAS

Renin-angiotensin-aldosterone system

RyR

Ryanodine receptor

SERCA

Sarcoplasmic/endoplasmic reticulum calcium ATPase

SR

Sarcoplasmic reticulum

STAT

Signal transducer and activator of transcription

T3

3,5,3′-triiodothyronine

T4

3,5,3′,5′-tetraiodothyronine

TGF-β

Transforming growth factor-β

TH

Thyroid hormone

TR

TH receptors

TβR

TGF-β receptors

VEGF

Vascular endothelial growth factor

VEGFR

VEGF receptor

VSMCs

Vascular smooth muscle cells

Notes

Acknowledgments

Thanks are due to the Portuguese Foundation for Science and Technology (FCT), European Union, QREN, FEDER and COMPETE for the financial support for the UnIC (UID/IC/00051/2019), iBiMED (UIDB/04501/2020) and CIAFEL (UIDB/00617/2020) research units and the research projects DOCnet (NORTE-01-0145-FEDER-000003) and NETDIAMOND (POCI‐01‐0145‐FEDER‐016385) and the post-graduation student (grant number SFRH/BD/111633/2015 to F.T.).

References

  1. 1.
    Bernardo BC, Weeks KL, Pretorius L, McMullen JR (2010) Molecular distinction between physiological and pathological cardiac hypertrophy: experimental findings and therapeutic strategies. Pharmacol Ther 128(1):191–227.  https://doi.org/10.1016/j.pharmthera.2010.04.005CrossRefGoogle Scholar
  2. 2.
    Tham YK, Bernardo BC, Ooi JY, Weeks KL, McMullen JR (2015) Pathophysiology of cardiac hypertrophy and heart failure: signaling pathways and novel therapeutic targets. Arch Toxicol 89(9):1401–1438.  https://doi.org/10.1007/s00204-015-1477-xCrossRefPubMedGoogle Scholar
  3. 3.
    Pinto AR, Ilinykh A, Ivey MJ, Kuwabara JT, D’Antoni ML, Debuque R, Chandran A, Wang L, Arora K, Rosenthal NA, Tallquist MD (2016) Revisiting cardiac cellular composition. Circ Res 118(3):400–409.  https://doi.org/10.1161/CIRCRESAHA.115.307778CrossRefPubMedGoogle Scholar
  4. 4.
    Maillet M, van Berlo JH, Molkentin JD (2013) Molecular basis of physiological heart growth: fundamental concepts and new players. Nat Rev Mol Cell Biol 14(1):38–48.  https://doi.org/10.1038/nrm3495CrossRefPubMedGoogle Scholar
  5. 5.
    Bers DM (2002) Cardiac excitation-contraction coupling. Nature 415(6868):198–205.  https://doi.org/10.1038/415198aCrossRefPubMedGoogle Scholar
  6. 6.
    Eisner DA, Caldwell JL, Kistamas K, Trafford AW (2017) Calcium and excitation-contraction coupling in the heart. Circ Res 121(2):181–195.  https://doi.org/10.1161/CIRCRESAHA.117.310230CrossRefPubMedGoogle Scholar
  7. 7.
    Mayourian J, Ceholski DK, Gonzalez DM, Cashman TJ, Sahoo S, Hajjar RJ, Costa KD (2018) Physiologic, pathologic, and therapeutic paracrine modulation of cardiac excitation-contraction coupling. Circ Res 122(1):167–183.  https://doi.org/10.1161/CIRCRESAHA.117.311589CrossRefPubMedGoogle Scholar
  8. 8.
    Kumari N, Gaur H, Bhargava A (2018) Cardiac voltage gated calcium channels and their regulation by beta-adrenergic signaling. Life Sci 194:139–149.  https://doi.org/10.1016/j.lfs.2017.12.033CrossRefPubMedGoogle Scholar
  9. 9.
    Duraes Campos I, Pinto V, Sousa N, Pereira VH (2018) A brain within the heart: a review on the intracardiac nervous system. J Mol Cell Cardiol 119:1–9.  https://doi.org/10.1016/j.yjmcc.2018.04.005CrossRefPubMedGoogle Scholar
  10. 10.
    Silvani A, Calandra-Buonaura G, Dampney RA, Cortelli P (2016) Brain-heart interactions: physiology and clinical implications. Philos Trans A Math Phys Eng Sci 374 (2067).  https://doi.org/10.1098/rsta.2015.0181CrossRefGoogle Scholar
  11. 11.
    Gordan R, Gwathmey JK, Xie L-H (2015) Autonomic and endocrine control of cardiovascular function. World J Cardiol 7(4):204–214.  https://doi.org/10.4330/wjc.v7.i4.204CrossRefPubMedGoogle Scholar
  12. 12.
    Lissandron V, Zaccolo M (2006) Compartmentalized cAMP/PKA signalling regulates cardiac excitation-contraction coupling. J Muscle Res Cell Motil 27(5–7):399–403.  https://doi.org/10.1007/s10974-006-9077-2CrossRefPubMedGoogle Scholar
  13. 13.
    Fu Q, Xiang YK (2015) Chapter Seven—Trafficking of β-adrenergic receptors: implications in intracellular receptor signaling. In: Wu G (ed) Progress in molecular biology and translational science, vol 132. Academic Press, pp 151–188.  https://doi.org/10.1016/bs.pmbts.2015.03.008Google Scholar
  14. 14.
    Lymperopoulos A, Rengo G, Koch WJ (2013) Adrenergic nervous system in heart failure: pathophysiology and therapy. Circ Res 113(6):739–753.  https://doi.org/10.1161/CIRCRESAHA.113.300308CrossRefPubMedGoogle Scholar
  15. 15.
    Harvey RD (2012) Muscarinic receptor agonists and antagonists: effects on cardiovascular function. Handb Exp Pharmacol 208:299–316.  https://doi.org/10.1007/978-3-642-23274-9_13CrossRefGoogle Scholar
  16. 16.
    Calvert JW, Condit ME, Aragon JP, Nicholson CK, Moody BF, Hood RL, Sindler AL, Gundewar S, Seals DR, Barouch LA, Lefer DJ (2011) Exercise protects against myocardial ischemia-reperfusion injury via stimulation of beta(3)-adrenergic receptors and increased nitric oxide signaling: role of nitrite and nitrosothiols. Circ Res 108(12):1448–1458.  https://doi.org/10.1161/CIRCRESAHA.111.241117CrossRefPubMedGoogle Scholar
  17. 17.
    Drawnel FM, Archer CR, Roderick HL (2013) The role of the paracrine/autocrine mediator endothelin-1 in regulation of cardiac contractility and growth. Br J Pharmacol 168(2):296–317.  https://doi.org/10.1111/j.1476-5381.2012.02195.xCrossRefPubMedGoogle Scholar
  18. 18.
    Bers DM, Guo T (2005) Calcium signaling in cardiac ventricular myocytes. Ann N Y Acad Sci 1047:86–98.  https://doi.org/10.1196/annals.1341.008CrossRefPubMedGoogle Scholar
  19. 19.
    Bers DM (2008) Calcium cycling and signaling in cardiac myocytes. Ann Rev Physiol 70(1):23–49.  https://doi.org/10.1146/annurev.physiol.70.113006.100455CrossRefGoogle Scholar
  20. 20.
    Maier LS, Bers DM (2007) Role of Ca2+/calmodulin-dependent protein kinase (CaMK) in excitation–contraction coupling in the heart. Cardiovasc Res 73(4):631–640.  https://doi.org/10.1016/j.cardiores.2006.11.005CrossRefPubMedGoogle Scholar
  21. 21.
    Dewenter M, von der Lieth A, Katus HA, Backs J (2017) Calcium signaling and transcriptional regulation in cardiomyocytes. Circ Res 121(8):1000–1020.  https://doi.org/10.1161/CIRCRESAHA.117.310355CrossRefPubMedGoogle Scholar
  22. 22.
    Schaub MC, Hefti MA, Zaugg M (2006) Integration of calcium with the signaling network in cardiac myocytes. J Mol Cell Cardiol 41(2):183–214.  https://doi.org/10.1016/j.yjmcc.2006.04.005CrossRefPubMedGoogle Scholar
  23. 23.
    Capote LA, Mendez Perez R, Lymperopoulos A (2015) GPCR signaling and cardiac function. Eur J Pharmacol 763(Pt B):143–148.  https://doi.org/10.1016/j.ejphar.2015.05.019CrossRefPubMedGoogle Scholar
  24. 24.
    Frelin C (1991) Mechanisms of vasoconstriction. Am Heart J 121 (3, Part 1):958–960.  https://doi.org/10.1016/0002-8703(91)90226-8CrossRefGoogle Scholar
  25. 25.
    Heineke J, Ritter O (2012) Cardiomyocyte calcineurin signaling in subcellular domains: from the sarcolemma to the nucleus and beyond. J Mol Cell Cardiol 52(1):62–73.  https://doi.org/10.1016/j.yjmcc.2011.10.018CrossRefPubMedGoogle Scholar
  26. 26.
    Sandoo A, van Zanten JJCSV, Metsios GS, Carroll D, Kitas GD (2010) The endothelium and its role in regulating vascular tone. Open Cardiovasc Med J 4:302–312.  https://doi.org/10.2174/1874192401004010302CrossRefPubMedGoogle Scholar
  27. 27.
    Khaddaj Mallat R, Mathew John C, Kendrick DJ, Braun AP (2017) The vascular endothelium: a regulator of arterial tone and interface for the immune system. Crit Rev Clin Lab Sci 54(7–8):458–470.  https://doi.org/10.1080/10408363.2017.1394267CrossRefPubMedGoogle Scholar
  28. 28.
    Conti V, Russomanno G, Corbi G, Izzo V, Vecchione C, Filippelli A (2013) Adrenoreceptors and nitric oxide in the cardiovascular system. Front Physiol 4:321.  https://doi.org/10.3389/fphys.2013.00321CrossRefPubMedGoogle Scholar
  29. 29.
    Morgado M, Cairrão E, Santos-Silva AJ, Verde I (2012) Cyclic nucleotide-dependent relaxation pathways in vascular smooth muscle. Cell Mol Life Sci 69(2):247–266.  https://doi.org/10.1007/s00018-011-0815-2CrossRefPubMedGoogle Scholar
  30. 30.
    Schlossmann J, Feil R, Hofmann F (2003) Signaling through NO and cGMP-dependent protein kinases. Ann Med 35(1):21–27. https://doi.org/10.1080/07853890310004093CrossRefGoogle Scholar
  31. 31.
    Ferreira R, Nogueira-Ferreira R, Trindade F, Vitorino R, Powers SK, Moreira-Gonçalves D (2018) Sugar or fat: the metabolic choice of the trained heart. Metabol Clin Exp 87:98–104.  https://doi.org/10.1016/j.metabol.2018.07.004CrossRefGoogle Scholar
  32. 32.
    Israeli-Rosenberg S, Manso AM, Okada H, Ross RS (2014) Integrins and integrin-associated proteins in the cardiac myocyte. Circ Res 114(3):572–586.  https://doi.org/10.1161/CIRCRESAHA.114.301275CrossRefPubMedGoogle Scholar
  33. 33.
    Haque ZK, Wang D-Z (2017) How cardiomyocytes sense pathophysiological stresses for cardiac remodeling. Cell Mol Life Sci 74(6):983–1000.  https://doi.org/10.1007/s00018-016-2373-0CrossRefPubMedGoogle Scholar
  34. 34.
    Samarel AM (2005) Costameres, focal adhesions, and cardiomyocyte mechanotransduction. Am J Physiol Heart Circ Physiol 289(6):H2291–H2301.  https://doi.org/10.1152/ajpheart.00749.2005CrossRefPubMedGoogle Scholar
  35. 35.
    Ross RS, Borg TK (2001) Integrins and the myocardium. Circ Res 88(11):1112–1119. https://doi.org/10.1161/hh1101.091862CrossRefGoogle Scholar
  36. 36.
    Wolfgang HG, José Luis A (2016) Cellular mechanotransduction. AIMS Biophys 3(1):50–62.  https://doi.org/10.3934/biophy.2016.1.50CrossRefGoogle Scholar
  37. 37.
    Buyandelger B, Mansfield C, Knöll R (2014) Mechano-signaling in heart failure. Pflugers Arch 466(6):1093–1099.  https://doi.org/10.1007/s00424-014-1468-4CrossRefPubMedGoogle Scholar
  38. 38.
    Dostal DE, Feng H, Nizamutdinov D, Golden HB, Afroze SH, Dostal JD, Jacob JC, Foster DM, Tong C, Glaser S, Gerilechaogetu F (2014) Mechanosensing and regulation of cardiac function. J Clin Exp Cardiol 5(6):314.  https://doi.org/10.4172/2155-9880.1000314CrossRefGoogle Scholar
  39. 39.
    De Acetis M, Notte A, Accornero F, Selvetella G, Brancaccio M, Vecchione C, Sbroggio M, Collino F, Pacchioni B, Lanfranchi G, Aretini A, Ferretti R, Maffei A, Altruda F, Silengo L, Tarone G, Lembo G (2005) Cardiac overexpression of melusin protects from dilated cardiomyopathy due to long-standing pressure overload. Circ Res 96(10):1087–1094.  https://doi.org/10.1161/01.RES.0000168028.36081.e0CrossRefPubMedGoogle Scholar
  40. 40.
    Sbroggiò M, Bertero A, Velasco S, Fusella F, De Blasio E, Bahou WF, Silengo L, Turco E, Brancaccio M, Tarone G (2011) ERK1/2 activation in heart is controlled by melusin, focal adhesion kinase and the scaffold protein IQGAP1. J Cell Sci 124(20):3515–3524.  https://doi.org/10.1242/jcs.091140CrossRefPubMedGoogle Scholar
  41. 41.
    Stiber JA, Seth M, Rosenberg PB (2009) Mechanosensitive channels in striated muscle and the cardiovascular system: not quite a stretch anymore. J Cardiovasc Pharmacol 54(2):116–122.  https://doi.org/10.1097/FJC.0b013e3181aa233fCrossRefPubMedGoogle Scholar
  42. 42.
    Patel A, Sharif-Naeini R, Folgering JR, Bichet D, Duprat F, Honore E (2010) Canonical TRP channels and mechanotransduction: from physiology to disease states. Pflugers Arch 460(3):571–581.  https://doi.org/10.1007/s00424-010-0847-8CrossRefPubMedGoogle Scholar
  43. 43.
    Sharif-Naeini R, Folgering JH, Bichet D, Duprat F, Delmas P, Patel A, Honore E (2010) Sensing pressure in the cardiovascular system: Gq-coupled mechanoreceptors and TRP channels. J Mol Cell Cardiol 48(1):83–89.  https://doi.org/10.1016/j.yjmcc.2009.03.020CrossRefPubMedGoogle Scholar
  44. 44.
    Lyon RC, Zanella F, Omens JH, Sheikh F (2015) Mechanotransduction in cardiac hypertrophy and failure. Circ Res 116(8):1462–1476.  https://doi.org/10.1161/CIRCRESAHA.116.304937CrossRefPubMedGoogle Scholar
  45. 45.
    Krüger M, Linke WA (2009) Titin-based mechanical signalling in normal and failing myocardium. J Mol Cell Cardiol 46(4):490–498.  https://doi.org/10.1016/j.yjmcc.2009.01.004CrossRefPubMedGoogle Scholar
  46. 46.
    Voelkel T, Linke WA (2011) Conformation-regulated mechanosensory control via titin domains in cardiac muscle. Pflugers Arch 462(1):143–154.  https://doi.org/10.1007/s00424-011-0938-1CrossRefPubMedGoogle Scholar
  47. 47.
    Linke WA (2008) Sense and stretchability: the role of titin and titin-associated proteins in myocardial stress-sensing and mechanical dysfunction. Cardiovasc Res 77(4):637–648.  https://doi.org/10.1016/j.cardiores.2007.03.029CrossRefPubMedGoogle Scholar
  48. 48.
    Kotter S, Andresen C, Kruger M (2014) Titin: central player of hypertrophic signaling and sarcomeric protein quality control. Biol Chem 395(11):1341–1352.  https://doi.org/10.1515/hsz-2014-0178CrossRefPubMedGoogle Scholar
  49. 49.
    Linke WA, Hamdani N (2014) Gigantic business. Circ Res 114(6):1052–1068.  https://doi.org/10.1161/CIRCRESAHA.114.301286CrossRefPubMedGoogle Scholar
  50. 50.
    Hamdani N, Herwig M, Linke WA (2017) Tampering with springs: phosphorylation of titin affecting the mechanical function of cardiomyocytes. Biophys Rev 9(3):225–237.  https://doi.org/10.1007/s12551-017-0263-9CrossRefPubMedGoogle Scholar
  51. 51.
    Shah R (2007) Endothelins in health and disease. Eur J Intern Med 18(4):272–282.  https://doi.org/10.1016/j.ejim.2007.04.002CrossRefPubMedGoogle Scholar
  52. 52.
    Houde M, Desbiens L, D’Orleans-Juste P (2016) Endothelin-1: biosynthesis, signaling and vasoreactivity. Adv Pharmacol 77:143–175.  https://doi.org/10.1016/bs.apha.2016.05.002CrossRefGoogle Scholar
  53. 53.
    Horinouchi T, Terada K, Higashi T, Miwa S (2013) Endothelin receptor signaling: new insight into its regulatory mechanisms. J Pharmacol Sci 123(2):85–101.  https://doi.org/10.1254/jphs.13R02CRCrossRefPubMedGoogle Scholar
  54. 54.
    Rodriguez-Pascual F, Busnadiego O, Lagares D, Lamas S (2011) Role of endothelin in the cardiovascular system. Pharmacol Res 63(6):463–472.  https://doi.org/10.1016/j.phrs.2011.01.014CrossRefPubMedGoogle Scholar
  55. 55.
    Foster SR, Roura E, Molenaar P, Thomas WG (2015) G protein-coupled receptors in cardiac biology: old and new receptors. Biophys Rev 7(1):77–89.  https://doi.org/10.1007/s12551-014-0154-2CrossRefPubMedGoogle Scholar
  56. 56.
    Mehta PK, Griendling KK (2007) Angiotensin II cell signaling: physiological and pathological effects in the cardiovascular system. Am J Physiol Cell Physiol 292(1):C82–C97.  https://doi.org/10.1152/ajpcell.00287.2006CrossRefPubMedGoogle Scholar
  57. 57.
    Balakumar P, Jagadeesh G (2014) A century old renin-angiotensin system still grows with endless possibilities: AT1 receptor signaling cascades in cardiovascular physiopathology. Cell Signal 26(10):2147–2160.  https://doi.org/10.1016/j.cellsig.2014.06.011CrossRefPubMedGoogle Scholar
  58. 58.
    Kawai T, Forrester SJ, O’Brien S, Baggett A, Rizzo V, Eguchi S (2017) AT1 receptor signaling pathways in the cardiovascular system. Pharmacol Res 125(Pt A):4–13.  https://doi.org/10.1016/j.phrs.2017.05.008CrossRefPubMedGoogle Scholar
  59. 59.
    Kerkela R, Ulvila J, Magga J (2015) Natriuretic peptides in the regulation of cardiovascular physiology and metabolic events. J Am Heart Assoc 4(10):e002423.  https://doi.org/10.1161/JAHA.115.002423CrossRefPubMedGoogle Scholar
  60. 60.
    Yasue H, Yoshimura M, Sumida H, Kikuta K, Kugiyama K, Jougasaki M, Ogawa H, Okumura K, Mukoyama M, Nakao K (1994) Localization and mechanism of secretion of B-type natriuretic peptide in comparison with those of A-type natriuretic peptide in normal subjects and patients with heart failure. Circulation 90(1):195–203. https://doi.org/10.1161/01.CIR.90.1.195CrossRefGoogle Scholar
  61. 61.
    Maisel AS, Duran JM, Wettersten N (2018) Natriuretic peptides in heart failure: atrial and B-type natriuretic peptides. Heart Fail Clin 14(1):13–25.  https://doi.org/10.1016/j.hfc.2017.08.002CrossRefPubMedGoogle Scholar
  62. 62.
    Woodard GE, Rosado JA (2008) Natriuretic peptides in vascular physiology and pathology. Int Rev Cell Mol Biol 268:59–93.  https://doi.org/10.1016/S1937-6448(08)00803-4CrossRefPubMedGoogle Scholar
  63. 63.
    Zois NE, Bartels ED, Hunter I, Kousholt BS, Olsen LH, Goetze JP (2014) Natriuretic peptides in cardiometabolic regulation and disease. Nat Rev Cardiol 11:403.  https://doi.org/10.1038/nrcardio.2014.64CrossRefPubMedGoogle Scholar
  64. 64.
    Janssen R, Muller A, Simonides WS (2017) Cardiac thyroid hormone metabolism and heart failure. Eur Thyroid J 6(3):130–137.  https://doi.org/10.1159/000469708CrossRefPubMedGoogle Scholar
  65. 65.
    Razvi S, Jabbar A, Pingitore A, Danzi S, Biondi B, Klein I, Peeters R, Zaman A, Iervasi G (2018) Thyroid hormones and cardiovascular function and diseases. J Am Coll Cardiol 71(16):1781–1796.  https://doi.org/10.1016/j.jacc.2018.02.045CrossRefPubMedGoogle Scholar
  66. 66.
    Rutigliano G, Zucchi R (2017) Cardiac actions of thyroid hormone metabolites. Mol Cell Endocrinol 458:76–81.  https://doi.org/10.1016/j.mce.2017.01.003CrossRefPubMedGoogle Scholar
  67. 67.
    Dan GA (2016) Thyroid hormones and the heart. Heart Fail Rev 21(4):357–359.  https://doi.org/10.1007/s10741-016-9555-6CrossRefPubMedGoogle Scholar
  68. 68.
    Gerdes AM, Ojamaa K (2016) Thyroid hormone and cardioprotection. Compr Physiol 6(3):1199–1219.  https://doi.org/10.1002/cphy.c150012CrossRefPubMedGoogle Scholar
  69. 69.
    Ojamaa K (2010) Signaling mechanisms in thyroid hormone-induced cardiac hypertrophy. Vascul Pharmacol 52(3–4):113–119.  https://doi.org/10.1016/j.vph.2009.11.008CrossRefPubMedGoogle Scholar
  70. 70.
    Brownsey RW, Boone AN, Allard MF (1997) Actions of insulin on the mammalian heart: metabolism, pathology and biochemical mechanisms. Cardiovasc Res 34(1):3–24.  https://doi.org/10.1016/S0008-6363(97)00051-5CrossRefPubMedGoogle Scholar
  71. 71.
    Riehle C, Abel ED (2016) Insulin signaling and heart failure. Circ Res 118(7):1151–1169.  https://doi.org/10.1161/CIRCRESAHA.116.306206CrossRefPubMedGoogle Scholar
  72. 72.
    DeBosch BJ, Muslin AJ (2008) Insulin signaling pathways and cardiac growth. J Mol Cell Cardiol 44(5):855–864.  https://doi.org/10.1016/j.yjmcc.2008.03.008CrossRefPubMedGoogle Scholar
  73. 73.
    Troncoso R, Ibarra C, Vicencio JM, Jaimovich E, Lavandero S (2014) New insights into IGF-1 signaling in the heart. Trends Endocrinol Metab 25(3):128–137.  https://doi.org/10.1016/j.tem.2013.12.002CrossRefPubMedGoogle Scholar
  74. 74.
    Laviola L, Natalicchio A, Giorgino F (2007) The IGF-I signaling pathway. Curr Pharm Des 13(7):663–669.  https://doi.org/10.2174/138161207780249146CrossRefPubMedGoogle Scholar
  75. 75.
    Hefti MA, Harder BA, Eppenberger HM, Schaub MC (1997) Signaling pathways in cardiac myocyte hypertrophy. J Mol Cell Cardiol 29(11):2873–2892.  https://doi.org/10.1006/jmcc.1997.0523CrossRefPubMedGoogle Scholar
  76. 76.
    Guo CA, Guo S (2017) Insulin receptor substrate signaling controls cardiac energy metabolism and heart failure. J Endocrinol 233(3):R131–R143.  https://doi.org/10.1530/JOE-16-0679CrossRefPubMedGoogle Scholar
  77. 77.
    Nakamura M, Sadoshima J (2018) Mechanisms of physiological and pathological cardiac hypertrophy. Nat Rev Cardiol 15(7):387–407.  https://doi.org/10.1038/s41569-018-0007-yCrossRefPubMedGoogle Scholar
  78. 78.
    Foncea R, Andersson M, Ketterman A, Blakesley V, Sapag-Hagar M, Sugden PH, LeRoith D, Lavandero S (1997) Insulin-like growth factor-I rapidly activates multiple signal transduction pathways in cultured rat cardiac myocytes. J Biol Chem 272(31):19115–19124. https://doi.org/10.1074/jbc.272.31.19115CrossRefGoogle Scholar
  79. 79.
    Moses AC (2005) Insulin resistance and type 2 diabetes mellitus: is there a therapeutic role for IGF-1? Endocr Dev 9:121–134.  https://doi.org/10.1159/000085762CrossRefGoogle Scholar
  80. 80.
    Zhang Y, Yuan M, Bradley KM, Dong F, Anversa P, Ren J (2012) Insulin-like growth factor 1 alleviates high-fat diet-induced myocardial contractile dysfunction: role of insulin signaling and mitochondrial function. Hypertension (Dallas, TX, 1979) 59(3):680–693.  https://doi.org/10.1161/hypertensionaha.111.181867CrossRefGoogle Scholar
  81. 81.
    Reboucas JS, Santos-Magalhaes NS, Formiga FR (2016) Cardiac regeneration using growth factors: advances and challenges. Arq Bras Cardiol 107(3):271–275.  https://doi.org/10.5935/abc.20160097CrossRefPubMedGoogle Scholar
  82. 82.
    Hausenloy DJ, Yellon DM (2009) Cardioprotective growth factors. Cardiovasc Res 83(2):179–194.  https://doi.org/10.1093/cvr/cvp062CrossRefPubMedGoogle Scholar
  83. 83.
    Itoh N, Ohta H (2013) Pathophysiological roles of FGF signaling in the heart. Front Physiol 4:247.  https://doi.org/10.3389/fphys.2013.00247CrossRefPubMedGoogle Scholar
  84. 84.
    Palmen M, Daemen MJ, De Windt LJ, Willems J, Dassen WR, Heeneman S, Zimmermann R, Van Bilsen M, Doevendans PA (2004) Fibroblast growth factor-1 improves cardiac functional recovery and enhances cell survival after ischemia and reperfusion: a fibroblast growth factor receptor, protein kinase C, and tyrosine kinase-dependent mechanism. J Am Coll Cardiol 44(5):1113–1123.  https://doi.org/10.1016/j.jacc.2004.05.067CrossRefPubMedGoogle Scholar
  85. 85.
    Leifheit-Nestler M, Haffner D (2018) Paracrine effects of FGF23 on the heart. Front Endocrinol (Lausanne) 9:278.  https://doi.org/10.3389/fendo.2018.00278CrossRefGoogle Scholar
  86. 86.
    Kardami E, Jiang ZS, Jimenez SK, Hirst CJ, Sheikh F, Zahradka P, Cattini PA (2004) Fibroblast growth factor 2 isoforms and cardiac hypertrophy. Cardiovasc Res 63(3):458–466.  https://doi.org/10.1016/j.cardiores.2004.04.024CrossRefPubMedGoogle Scholar
  87. 87.
    House SL, Branch K, Newman G, Doetschman T, Schultz Jel J (2005) Cardioprotection induced by cardiac-specific overexpression of fibroblast growth factor-2 is mediated by the MAPK cascade. Am J Physiol Heart Circ Physiol 289(5):H2167–H2175.  https://doi.org/10.1152/ajpheart.00392.2005CrossRefPubMedGoogle Scholar
  88. 88.
    Tanajak P, Chattipakorn SC, Chattipakorn N (2015) Effects of fibroblast growth factor 21 on the heart. J Endocrinol 227(2):R13–R30.  https://doi.org/10.1530/JOE-15-0289CrossRefPubMedGoogle Scholar
  89. 89.
    Liang P, Zhong L, Gong L, Wang J, Zhu Y, Liu W, Yang J (2017) Fibroblast growth factor 21 protects rat cardiomyocytes from endoplasmic reticulum stress by promoting the fibroblast growth factor receptor 1-extracellular signal regulated kinase 1/2 signaling pathway. Int J Mol Med 40(5):1477–1485.  https://doi.org/10.3892/ijmm.2017.3140CrossRefPubMedGoogle Scholar
  90. 90.
    Lal N, Puri K, Rodrigues B (2018) Vascular endothelial growth factor B and its signaling. Front Cardiovasc Med 5:39.  https://doi.org/10.3389/fcvm.2018.00039CrossRefPubMedGoogle Scholar
  91. 91.
    Smith GA, Fearnley GW, Tomlinson DC, Harrison MA, Ponnambalam S (2015) The cellular response to vascular endothelial growth factors requires co-ordinated signal transduction, trafficking and proteolysis. Biosci Rep 35(5).  https://doi.org/10.1042/bsr20150171
  92. 92.
    Smith GA, Fearnley GW, Harrison MA, Tomlinson DC, Wheatcroft SB, Ponnambalam S (2015) Vascular endothelial growth factors: multitasking functionality in metabolism, health and disease. J Inherit Metab Dis 38(4):753–763.  https://doi.org/10.1007/s10545-015-9838-4CrossRefPubMedGoogle Scholar
  93. 93.
    Bates DO (2010) Vascular endothelial growth factors and vascular permeability. Cardiovasc Res 87(2):262–271.  https://doi.org/10.1093/cvr/cvq105CrossRefPubMedGoogle Scholar
  94. 94.
    Heldin CH, Ostman A, Ronnstrand L (1998) Signal transduction via platelet-derived growth factor receptors. Biochim Biophys Acta 1378(1):F79–F113.  https://doi.org/10.1016/S0304-419X(98)00015-8CrossRefPubMedGoogle Scholar
  95. 95.
    Medamana J, Clark RA, Butler J (2017) Platelet-derived growth factor in heart failure. Handb Exp Pharmacol 243:355–369.  https://doi.org/10.1007/164_2016_80CrossRefPubMedGoogle Scholar
  96. 96.
    Raines EW (2004) PDGF and cardiovascular disease. Cytokine Growth Factor Rev 15(4):237–254.  https://doi.org/10.1016/j.cytogfr.2004.03.004CrossRefPubMedGoogle Scholar
  97. 97.
    Bornfeldt KE, Raines EW, Graves LM, Skinner MP, Krebs EG, Ross R (1995) Platelet-derived growth factor. Distinct signal transduction pathways associated with migration versus proliferation. Ann N Y Acad Sci 766:416–430.  https://doi.org/10.1111/j.1749-6632.1995.tb26691.xCrossRefPubMedGoogle Scholar
  98. 98.
    Fuller SJ, Sivarajah K, Sugden PH (2008) ErbB receptors, their ligands, and the consequences of their activation and inhibition in the myocardium. J Mol Cell Cardiol 44(5):831–854.  https://doi.org/10.1016/j.yjmcc.2008.02.278CrossRefPubMedGoogle Scholar
  99. 99.
    Pentassuglia L, Sawyer DB (2009) The role of Neuregulin-1β/ErbB signaling in the heart. Exp Cell Res 315(4):627–637.  https://doi.org/10.1016/j.yexcr.2008.08.015CrossRefPubMedGoogle Scholar
  100. 100.
    Wadugu B, Kuhn B (2012) The role of neuregulin/ErbB2/ErbB4 signaling in the heart with special focus on effects on cardiomyocyte proliferation. Am J Physiol Heart Circ Physiol 302(11):H2139–H2147.  https://doi.org/10.1152/ajpheart.00063.2012CrossRefPubMedGoogle Scholar
  101. 101.
    Goumans MJ, Ten Dijke P (2018) TGF-beta signaling in control of cardiovascular function. Cold Spring Harb Perspect Biol 10(2).  https://doi.org/10.1101/cshperspect.a022210CrossRefGoogle Scholar
  102. 102.
    Bujak M, Frangogiannis NG (2007) The role of TGF-beta signaling in myocardial infarction and cardiac remodeling. Cardiovasc Res 74(2):184–195.  https://doi.org/10.1016/j.cardiores.2006.10.002CrossRefPubMedGoogle Scholar
  103. 103.
    Agrotis A, Kalinina N, Bobik A (2005) Transforming growth factor-beta, cell signaling and cardiovascular disorders. Curr Vasc Pharmacol 3(1):55–61. https://doi.org/10.2174/1570161052773951CrossRefGoogle Scholar
  104. 104.
    Dobaczewski M, Chen W, Frangogiannis NG (2011) Transforming growth factor (TGF)-beta signaling in cardiac remodeling. J Mol Cell Cardiol 51(4):600–606.  https://doi.org/10.1016/j.yjmcc.2010.10.033CrossRefPubMedGoogle Scholar
  105. 105.
    Brand T, Schneider MD (1995) The TGF beta superfamily in myocardium: ligands, receptors, transduction, and function. J Mol Cell Cardiol 27(1):5–18.  https://doi.org/10.1016/S0022-2828(08)80003-XCrossRefPubMedGoogle Scholar
  106. 106.
    Frangogiannis NG (2018) Cardiac fibrosis: cell biological mechanisms, molecular pathways and therapeutic opportunities. Mol Asp Med.  https://doi.org/10.1016/j.mam.2018.07.001CrossRefGoogle Scholar
  107. 107.
    MacLean J, Pasumarthi KB (2014) Signaling mechanisms regulating fibroblast activation, phenoconversion and fibrosis in the heart. Indian J Biochem Biophys 51(6):476–482PubMedGoogle Scholar
  108. 108.
    de Souza RR (2002) Aging of myocardial collagen. Biogerontology 3(6):325–335.  https://doi.org/10.1023/A:1021312027486CrossRefPubMedGoogle Scholar
  109. 109.
    Guo Y, Gupte M, Umbarkar P, Singh AP, Sui JY, Force T, Lal H (2017) Entanglement of GSK-3β, β-catenin and TGF-β1 signaling network to regulate myocardial fibrosis. J Mol Cell Cardiol 110:109–120.  https://doi.org/10.1016/j.yjmcc.2017.07.011CrossRefPubMedGoogle Scholar
  110. 110.
    Diaz-Araya G, Vivar R, Humeres C, Boza P, Bolivar S, Munoz C (2015) Cardiac fibroblasts as sentinel cells in cardiac tissue: receptors, signaling pathways and cellular functions. Pharmacol Res 101:30–40.  https://doi.org/10.1016/j.phrs.2015.07.001CrossRefPubMedGoogle Scholar
  111. 111.
    Zent J, Guo LW (2018) Signaling mechanisms of myofibroblastic activation: outside-in and inside-out. Cell Physiol Biochem 49(3):848–868.  https://doi.org/10.1159/000493217CrossRefGoogle Scholar
  112. 112.
    Somanna NK, Yariswamy M, Garagliano JM, Siebenlist U, Mummidi S, Valente AJ, Chandrasekar B (2015) Aldosterone-induced cardiomyocyte growth, and fibroblast migration and proliferation are mediated by TRAF3IP2. Cell Signal 27(10):1928–1938.  https://doi.org/10.1016/j.cellsig.2015.07.001CrossRefPubMedGoogle Scholar
  113. 113.
    Hafizi S, Wharton J, Chester AH, Yacoub MH (2004) Profibrotic effects of endothelin-1 via the ETA receptor in cultured human cardiac fibroblasts. Cell Physiol Biochem 14(4–6):285–292.  https://doi.org/10.1159/000080338CrossRefPubMedGoogle Scholar
  114. 114.
    Hu HH, Chen DQ, Wang YN, Feng YL, Cao G, Vaziri ND, Zhao YY (2018) New insights into TGF-beta/Smad signaling in tissue fibrosis. Chem Biol Interact 292:76–83.  https://doi.org/10.1016/j.cbi.2018.07.008CrossRefPubMedGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2020

Authors and Affiliations

  • Fábio Trindade
    • 1
    • 2
    Email author
  • Inês Falcão-Pires
    • 1
  • Andreas Kavazis
    • 3
  • Adelino Leite-Moreira
    • 1
    • 4
  • Daniel Moreira-Gonçalves
    • 1
    • 5
  • Rita Nogueira-Ferreira
    • 1
    Email author
  1. 1.Department of Surgery and PhysiologyCardiovascular R&D Center, Faculty of Medicine of the University of PortoPortoPortugal
  2. 2.Department of Medical Sciences, iBiMED–Institute of BiomedicineUniversity of AveiroAveiroPortugal
  3. 3.School of KinesiologyAuburn UniversityAuburnUSA
  4. 4.Department of Cardiothoracic SurgeryCentro Hospitalar Universitário São JoãoPortoPortugal
  5. 5.Faculty of Sport, CIAFELUniversity of PortoPortoPortugal

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